Aspergillus fumigatus is an environmental mold that is responsible for a life-threatening pneumonia known as invasive aspergillosis. The infection begins with the inhalation of conidia (spores) into the lung. In a healthy individual, the spores are cleared by the immune system. However, in the immunosuppressed population, or patients in the ICU, failure to eradicate the fungus allows the spores to germinate. A. fumigatus releases an armamentarium of degradative enzymes as it grows, resulting in severe damage to the lung parenchyma. Fibroblasts are one of the major cell types that respond to tissue damage. In response to injury, these cells differentiate into an activated state, which is required to stabilize the tissue and promote repair. However, fibroblast activity is not restricted to matrix secretion; emerging evidence suggests that they also possess the ability to detect microbial pathogens and to respond by secreting mediators with the potential to contribute to pathogen clearance. In this grant, we propose to take advantage of unique genetic mouse models that we have developed to determine the contribution of pulmonary fibroblasts to the outcome of A. fumigatus exposure. We hypothesize that fibroblast activation in response to A. fumigatus-induced lung damage amplifies a protective inflammatory response. The proposed aims will test this hypothesis by determining the dynamics of fibroblast activation and deactivation in response to A. fumigatus in both immunocompetent and immunosuppressed mice, the transcriptional response of fibroblasts to A. fumigatus exposure, and the contribution of fibroblasts to pathogenic outcome in a mouse model of fibroblast ablation. The findings of this study will provide new information on mechanisms of host defense against A. fumigatus and potentially other pathogens that damage the human lung. 1

Project narrative Infections caused by the opportunistic fungal pathogen Aspergillus fumigatus range from a chronic inflammatory and fibrotic process known as chronic pulmonary aspergillus to an acute life-threatening pneumonia known as invasive aspergillosis. This study will employ newly developed model systems to understand how lung fibroblasts coordinate with the immune system to protect the lung from this infection, with the long-term goal of using this information as a foundation to develop novel treatment strategies to enhance pulmonary defenses.